Promising approaches in the search for biomarkers of bipolar disorder
Authors: Mary L. Phillips
Journal: World Psychiatry (2023)

Abi-Dargham et al1 highlight the critical gaps that exist in the validation of candidate biomarkers of major psychiatric disorders. They point out that one of the problems of several large consortia studies has been the absence of “actionable biomarker targets”, as studies have largely been designed to identify between-group differences and/or associations among measures rather than biomarkers for specific purposes such as risk prediction or treatment response. Further problems are the considerable heterogeneity of many of the major psychiatric disorders and the insufficiently precise measurement technologies. The authors make several recommendations regarding approaches that should be taken in future biomarker discovery and validation studies. One such approach is the focus on intermediate phenotypes that reflect underlying pathophysiological mechanisms better than diagnostic categories of illness. I would like to provide examples of how this approach can be implemented in the study of biomarkers of bipolar disorder. Probably because of the complex clinical presentation of this disorder, it has been especially difficult to identify neurobiological markers that reflect underlying pathophysiological mechanisms. I would argue, however, that it is possible to begin to meet this challenge by focusing on the study of neurobiological mechanisms underlying some key constructs that characterize the defining feature of bipolar disorder, i.e. mania/hypomania. A well-replicated literature indicates that mania/hypomania is characterized, and its onset and associated functional impairment predicted, by elevated reward sensitivity and goal overvaluation2, and impulsive decision-making and behavior3. These characteristics are closely associated with other clinical features of mania/hypomania, such as increased energy/reduced need for sleep, and exuberant/irritable mood. Focusing on those two characteristics is thus a way to identify the neurobiological mechanisms underlying mania/hypomania. The above characteristics can be triggered within reward expectancy contexts in individuals with bipolar disorder2. Two such reward expectancy contexts that can be modeled in experimental paradigms are: a) uncertain reward expectancy during goal (reward) pursuit, where the probability of an immediate future reward is varied and uncertain, and where potential future rewards will be overvalued by reward sensitive/goal overvaluation prone individuals2; and b) intertemporal decision-making, where a choice is made between an immediate smaller vs. a delayed larger reward option, based on the subjective value of these two options, and where reward-driven impulsive decision-making and behavior (i.e., choosing the often more disadvantageous immediate smaller reward) can be triggered in more impulsive individuals. Uncertain reward expectancy and intertemporal decision-making are thus ideal contexts for examining the neurobiological mechanisms underlying reward sensitivity/goal overvaluation and reward-driven impulsive decision-making and behavior. Dopamine transmission abnormalities likely underlie predisposition to the above key features of mania/hypomania, since amphetamine can induce mania/hypomania, and antipsychotic medications used to treat or prevent recurrence of mania/hypomania impact dopamine transmission4. Moreover, the prefrontal cortical-striatal reward neural network, which has been implicated in bipolar disorder and predisposition to mania/hypomania5, has extensive dopamine projections: midbrain ventral tegmental area to ventral striatum (mesolimbic), midbrain substantia nigra pars compacta to dorsal striatum (nigrostriatal), and ventral tegmental area to prefrontal cortex (mesocortical) pathways. Furthermore, amphetamine-induced ventral striatal dopamine release was positively associated with increase in mania/hypomania in adults with bipolar disorder vs. non-psychiatric control participants6; and a large rodent literature associates elevated reward network ventral tegmental area dopamine transmission with reward-driven impulsive behavior, as well as other features of mania/hypomania, such as reduced sleep and increased energy4. Together, these findings indicate that the combination of specific reward expectancy paradigms and multimodal imaging approaches examining reward expectancy-related neural network activity and underlying dopaminergic modulation is a promising way to identify biomarkers reflecting neurobiological mechanisms predisposing to mania/hypomania. Bipolar disorder has also been conceptualized as a disorder of energy regulation7, involving high levels of mitochondrial dysfunction and oxidative stress that might result from elevated dopamine transmission. Elegant translational work in mice and humans has shown that sustained elevated dopamine synthesis results in elevated cytosolic dopamine, which in turn leads to increased metabolism of dopamine by monoamine oxidase8. In this process, monoamine oxidase anchors to the outer mitochondrial membrane and transfers electrons generated by dopamine deamination into the mitochondrial inter-membrane space, increasing electron transport chain activity and supporting elevated dopamine synthesis and release. Increased metabolic demand can, however, ultimately lead to impaired mitochondrial function and a toxic cascade in which elevated oxidative stress-induced mitochondrial dysfunction results in cytosolic dopamine oxidation, with elevated cytosolic dopamine further contributing to mitochondrial oxidative stress9. Thus, elevated dopamine transmission and associated mitochondrial dysfunction is a putative mechanism underlying the energy regulation dysfunction characterizing mania/ hypomania in bipolar disorder. These examples provide possible approaches that can be adopted by future studies aiming to identify biomarkers reflecting core neurobiological mechanisms underlying key features characterizing and predisposing to mania/hypomania. An important point to note, however, is that these features, especially reward-driven impulsive decision-making and behavior, are associated, at least in part, with other disorders, such as substance use disorders. Thus, these approaches will likely yield biomarkers that are not necessarily specific to a given psychiatric disorder as currently defined by the DSM-5, but instead reflect neurobiological mechanisms underlying constructs that cut across different diagnostic categories. This transdiagnostic approach accords with the Research Domain Criteria model, where the two reward expectancy contexts described above link with two subconstructs of the Reward Valuation construct of Positive Valence Systems. As Abi-Dargham et al highlight in their paper, a given DSM-5-defined disorder may be associated with several different biomarkers, each reflecting a neurobiological mechanism related to a transdiagnostic construct, which may promote a move toward biologically-based classification systems in psychiatry. Clearly, there is a need for extensive work replicating findings in independent samples to ultimately provide robust and reliable biomarkers of any given disorder. Yet, I remain hopeful that with increasingly sophisticated neuroimaging methodologies (e.g., higher field strength magnetic resonance imaging), alongside better animal and cellular models, there is now an opportunity to elucidate neurobiological mechanisms of key transdiagnostic constructs and provide robust biomarkers to help shape new classification systems. This will yield targets to aid risk identification and help develop new interventions. As Abi-Dargham et al note, this is not only a major scientific goal in our field, but is also a critical clinical mission to improve the health and well-being of all of those suffering from these debilitating and yet common illnesses.